ErbB2, also known as v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2, Her2, Neu, CD340, proto-oncogene C-ErbB2, is a member of the extensively studied ErbB family of plasma membrane-bound receptor tyrosine kinases, which also includes ErbB1, ErbB3 and ErbB4 (also known as EGFR/Her1, Her3 and Her4, respectively). These receptors have been shown to play critical roles in embryonic development, normal physiology and the development of various diseases. All four ErbB receptors contain an extracellular domain (ECD), a transmembrane domain and an intracellular domain that interacts with signaling molecules. Ligand binding to the ECDs of these receptors leads to homo- or hetero-dimerization, followed by the activation of the intrinsic protein tyrosine kinase and tyrosine autophosphorylation in the intracellular domain, and recruitment and activation of signaling proteins to these sites. Notably, ErbB3 is kinase-impaired and requires heterodimerization for activation. To date, while multiple ligands have been identified for ErbB1, ErbB3 and ErbB4, no ligand for ErbB2 has been found, ever since its discovery nearly 30 years ago (Coussens et al. Science 1985; 230: 1132-1139; Schechter et al. Science 1985; 229: 976-978). However, ErbB2 is a preferred dimerization partner for other ligand-bound ErbBs.
ErbB2 is best known for its involvement in human breast cancer. ErbB2 gene amplification occurs in 20-30% of breast cancer and is significantly correlated with ErbB2 protein expression in the cancer tissues. ErbB2 gene amplification or protein overexpression is a strong predictor of poor disease prognosis. ErbB2-targeted therapies, particularly humanized monoclonal antibody trastuzumab in combination with chemotherapy, show considerable clinical efficacy. However, many ErbB2-positive cancers show de novo resistance or acquired resistance to such a therapy. Thus, there is an ongoing and unmet need to identify a ligand of ErbB2 and to develop therapeutic approaches based at least in part upon such a ligand. The present disclosure meets these needs.